Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction and pathologically by depletion of dopamine (DA)-producing neurons in the nigrostriatal DA (NSD) system. Environmental risk factors for PD are consistently reported, via epidemiological, clinical, and animal studies. Though PD typically emerges late in life, the environment in periods of neurodevelopment is gaining attention as a susceptibility factor. For example, in mice, prenatal exposure to the fungicide maneb (MB) greatly increased adulthood susceptibility to the pesticide paraquat (PQ), resulting in features of PD. Concordant with the mission of the NIEHS, the current proposal seeks to unravel the mechanism by which MB alters neurodevelopment to confer vulnerability to the progressive neurodegeneration seen in PD. To understand the role of multiple environmental hits, a cohort design will be employed in which mice prenatally exposed to MB will be followed across the lifespan, with intermittent exposure to PQ. Dopaminergic integrity will be assessed at many timepoints for evidence of progressive neurodegeneration, and toxicokinetic and toxicodynamic study of MB and PQ will be undertaken. It is hypothesized that prenatal MB exposure induces a state of altered potential (SAP), and that this SAP describes a pre-clinical phase of DAergic dysfunction. This SAP will be characterized through gene expression profiling and analysis of several biochemical systems (including those for DA homeostasis, oxidative stress response, trophic factors, and barriers);risk factors (e.g. aging, PQ) may act through these systems, and these endpoints will also be studied in the context of these risk factors. Finally, since gender plays a major role in PD, it is hypothesized that gonadal steroid hormones modulate risk;this will be assessed by characterizing the role of the estrous cycle on the normal mouse NSD system, on PQ toxicokinetics and toxicodynamics, and also by manipulating gonadal steroid exposure at various stages of development. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a major health concern, and though onset of symptoms typically occurs late in the lifespan, environmental factors as early as prenatal life may have long-lasting consequences for development of this disease. Using an animal model of prenatal exposure to the fungicide maneb, this proposal seeks 1. to understand how maneb creates long-lasting susceptibility, 2. to define the biochemical and gene expression profile that describes the pre-symptomatic state of vulnerability, and 3. to clarify the role of gender in mediating these effects. In addition to providing insight into the etiology of PD and contributing to risk assessment paradigms, we will identify stable targets that may be amenable to manipulation to modify risk and/or severity of PD.